Prostate cancer is the most common malignancy and the second leading cause of cancer death in males in the United States. Despite advances in localized therapy of prostate cancer, a significant fraction of men develop metastatic disease at some point in the course of the illness. We have previously studied treatment approaches for this disease which focus on the nuclear matrix and the DNA replication complex. This protocol will continue those studies using the topoisomerase I inhibitor irinotecan (CPT-11) in combination with estramustine. This is an open-label phase II trial. Up to 33 evaluable subjects will complete the study. Subjects will receive oral estramustine at a dose of 280 mg three times per day for seven days. On day 2 of subjects will receive intravenous CPT-11 over 90 minutes at a dose of 300 mg/m2. Treatment will be repeated at three week intervals.